This section introduces aspects that may help facilitate a better understanding of the disclosure. Accordingly, these statements are to be read in this light and are not to be understood as admissions about what is or is not prior art.
In humans, the immune response is a very complex process involved in defense against external pathogens or foreign tissues. Abnormalities in the human immune system often lead to disease states like cancer and autoimmune disorders (Chaplin, et al., J. Allergy Clin. Immunol. 2010, 125, S3-23; Cho, et al., Nat. Med. 2015, 21, 730-738). Autoimmune diseases are a group of diseases in which the immune system of an organism attacks body parts within the same organism. It is estimated that 24 million people are affected by autoimmune disease in the United States. Cytokines play essential roles in regulating the immune responses via cytokine-mediated gene activation or repression. The JAK-STAT pathway was discovered as a central player in the signal transduction cascade of many cytokines. Cytokine binding triggers receptor dimerization, which leads to JAK tyrosine kinase activation in which the two JAKs phosphorylate each other. JAK-mediated STAT phosphorylation subsequently induces dimerization of these signal transduction proteins and translocation to the nucleus, which initiates gene transcription (Rawlings, et al., J. Cell Sci. 2004, 117, 1281-1283). The JAK family has four members: JAK1, JAK2, JAK3 and TYK2. The JAKs are activated in specific patterns by different cytokines. JAK1 and JAK3 are activated by the members of the γ common (γc) subfamily, namely, interleukins IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 which can't activate JAK2 or TYK2. On the other hand, another subfamily of cytokines that contain the glycoprotein 130 (gp130) signal transducing subunit and includes IL-6, IL-11, IL-27, and several other cytokines that induce JAK1 activation, and JAK2 and TYK2 are also consistently engaged. Erythropoietin (EPO) receptors are another subfamily of homodimeric receptors that also includes the receptors for prolactin, thrombopoietin, and growth hormone. The EPO pathway activates JAK2 exclusively and is essential for erythropoiesis.
Since the discovery of the Janus family of kinases (JAKs) and their pivotal role in the immune system, they have attracted great interest for the development of new medications for various immune system-related disease. Over the past decade there have been extensive efforts to identify and design novel small-molecule JAK inhibitors with various profiles of subtype selectivity to address unmet medical needs such as transplant rejection, rheumatoid arthritis, cancers, and other autoimmune diseases (Clark, et al., J. Med. Chem. 2014, 57, 5023-5038). The selectivities of JAK inhibitors against the four family members and against other tyrosine kinases are very important. All of the current inhibitors are mixed inhibitors of all four kinases with varying potencies vs. each one (Furumoto, et al., BioDrugs: clinical immunotherapeutics, biopharmaceuticals and gene therapy 2013, 27, 431-438). Currently, two compounds have been approved by the FDA for the treatment of rheumatoid arthritis and organ transplant rejection, namely tofacitinib and ruxolitinib. These two compounds suffer from many side effects and more selective medications should be developed to overcome them (Yamaoka, et al., Curr. Opin. Chem. Biol. 2016, 32, 29-33; Boyce, et al., Patient Related Outcome Measures 2016, 7, 1-12). There are still unmet needs in those areas.
With regard to the design and synthesis of JAK inhibitors, it should be noted that Pd catalysis has offered new pathways for the preparation of pharmaceuticals. Tandem catalysis is a process in which the catalyst is used to catalyze more than one reaction for the construction of complex molecules from simple building blocks. In the present work, auto-tandem palladium catalysis was applied for the rapid construction of active JAK inhibitors with various selectivity and activities. This has made the synthesis of these compounds easier, it has allowed rapid diversification of newly designed scaffolds to obtain a wide range of activities and selectivity. Despite the extensive effort being made to discover safe and effective JAK kinases inhibitors, there is still a need for safer compounds with fewer side effects and higher selectivity. The rapid access to a focused library of active scaffolds will help to accelerate the identification of the best candidates for further development (Harris, et al., Comb. Chem. High Throughput Screening 2011, 14, 521-531).